Nalmefene is a known opioid receptor antagonist which can inhibit pharmacological effects of both administered opioid agonists and endogenous produced agonists from the opioid system. The clinical usefulness of Nalmefene as an antagonist comes from its ability to promptly (and selectively) reverse the effects of these opioid agonists, including the often observed depressions in the central nervous system and the respiratory system.
Nalmefene has primarily been developed for use in the management of alcohol dependence, where it has shown good effect in doses of 10 to 40 mg taken when the patient believed drinking to be imminent (about 1-2 hours before drinking) (Karhuvaara et al., Alcohol. Clin. Exp. Res., (2007), Vol. 31 No. 7. pp 1179-1187). Additionally, Nalmefene has also been investigated for the treatment of other addictions such as pathological gambling and addiction to shopping. In these developmental programs and testing, Nalmefene has been used, for example as a parental solution (Revex™).
Nalmefene is an opiate derivative similar in structure to the opiate antagonist Naltrexone. Advantages of Nalmefene relative to Naltrexone include longer half-life, greater oral bio availability and no observed dose-dependent liver toxicity.
Nalmefene differs from Naltrexone by substitution of the ketone group at the 6-position of Naltrexone with a methylene (CH2) group, which considerably increases binding affinity to the μ-opioid receptor. Nalmefene also has high affinity for the other opioid receptors (κ and δ receptors), and is known as a “universal antagonist” for its ability to block all three.
Nalmefene can be produced according to the method described by Hanh et al., (J. Med. Chem., 18, 259-262 (1975), Mallinckrodt (U.S. Pat. No. 4,751,307), and Meltzner et al., (U.S. Pat. No. 4,535,157).
By using the above-mentioned methods, the free base of Nalmefene is obtained, which subsequently can be converted into the hydrochloride salt, by use of conventional methods.
According to Brittain, (Analytical Profiles of Drug Substances and Excipients (1996), Vol 24, pp. 351-395) Nalmefene hydrochloride can be recrystallized from water, giving a pure drug substance, which inevitably consists of a monohydrate crystal phase. In the same review the monohydrate phase of Nalmefene hydrochloride is described as essentially non-hygroscopic since it can only sorb up to 1% of adventitious moisture.
The inventors of the present invention have found that, contrary to the literature, Nalmefene hydrochloride as a monohydrate is hygroscopic.
There is therefore a need for providing a novel, stable and non-hygroscopic hydrate form of Nalamefene and methods for its manufacturing.